Polymer-particle light-cleavable carrier systems for photodynamic therapy

Abstract

The present invention generally relates to the formation, chemistry and application of biologically active compositions. More particularly, the present invention relates to certain dyes, specifically porphyrin and chlorin derivatives, in combination with inventive polymers, i.e. light-cleavable polymers, that can be used as photosensitizer compositions for a wide range of light irradiation treatments such as photodynamic therapy of cancer, infections and other diseases. The dye derivatives may either be adsorbed on, or incorporated in, or attached to specific polymers, which as well form part of the invention.

The invention claimed is: 
     
       1. A polymer, selected from the group consisting of
 a polycarbonate of formula 10 
 
       
         
           
           
               
               
           
         
         wherein n=0 or 1; x=+5-1000; 
         R 1  is H or an alkyl chain with 1 to 5 carbon atoms; 
         R 2  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         R 3  is a divalent radical selected from the group consisting of an alkyl, aryl and alkylene group having 1 to 10 carbon atoms;
 a block copolymer of formula 12 
 
       
       
         
           
           
               
               
           
         
         wherein n=0 or 1; x=45-1000; y=1-1000; 
         R 1  is H or an alkyl chain with 1 to 5 carbon atoms; 
         R 2  is selected from the groups consisting of 
       
       
         
           
           
               
               
           
         
         R 3  is a divalent radical selected from the group consisting of an alkyl, aryl and alkylene group having 1 to 10 carbon atoms; and
 a polyester of formula 13 
 
       
       
         
           
           
               
               
           
         
         wherein n=0 or 1; x=5−1000; 
         R 1  is H or an alkyl chain with 1 to 5 carbon atoms; 
         R 2  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         R 3  is selected from the group consisting of an alkyl, aryl and alkylene group having 1 to 10 carbon atoms. 
       
     
     
       2. A pharmaceutical composition, comprising
 a light-cleavable polymer formed as nanometer particles, wherein the light-cleavable polymer comprises a polymer according to  claim 1 ; 
 a therapeutically effective amount of a photosensitizer. 
 
     
     
       3. A pharmaceutical composition according to  claim 2 , characterized in that the photosensitizer is a tetrapyrrole-based photosensitizer. 
     
     
       4. A pharmaceutical composition according to  claim 3 , characterized in that the photosensitizer is a chlorin or bacteriochlorin derivative according to formula A 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or OH; 
         R 2  to R 5  are different or the same and comprise substituents either in the meta- or para-position of the phenyl ring with R 2  to R 5  independently of one another selected Y is a peptide or an oligopeptide wherein the n in formulas 10, 12 and 13=1-30; 
         from the group consisting of —OH, —COOH, —NH 2 , —COOX, —NHX, OX, —NH—Y—COOH, and —CO—Y—NH 2 ; 
         wherein 
         X is (CH 2 CH 2 O) n , CH 3  with the n in (CH 2 CH 2 O) n CH 3 =1−30 or a carbohydrate moiety; 
         Y is a peptide or an oligopeptide wherein the x in formulas 10, 12 and 13=5−30; 
         ring D has a structure selected from 
       
       
         
           
           
               
               
           
         
       
     
     
       5. A pharmaceutical composition according to  claim 2 , characterized in that the photosensitizer is present in an amount of 1 to 500 μg per mg light cleavable polymer. 
     
     
       6. A pharmaceutical composition according to  claim 2 , characterized in that the photosensitizer is a tetrapyrrolic compound of formulas 14, 15, 16, 17, 18 or 19 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         B is selected from 
       
       
         
           
           
               
               
           
         
         X is NH, O or S; 
         R 1  is a linear or branched alkyl chain with 3-4 carbon atoms and containing at least two hydroxyl moieties; 
         R 2  is a substituent either in the meta- or para-position of the phenyl ring wherein 
         R 2  is —OH, —COOH, —COOY, —NHY, OY, —NH—Z—COOH, or —CO—Z—NH 2 ; 
         wherein 
         Y is (CH 2 CH 2 O) n CH 3  with the n in (CH 2 CH 2 O) n CH 3 =1-30 or a carbohydrate moiety; and 
         Z is selected from a peptide or an oligopeptide wherein the x in formulas 10, 12 and 13=5−30. 
       
     
     
       7. A method of forming a pharmaceutical composition according to  claim 2 , comprising the steps of:
 a) dissolving the light-cleavable polymer alone or in combination with a further polymer in an organic solvent to form a polymer solution; 
 b) optionally dissolving a stabilizer in an aqueous solution to form a stabilizing solution; 
 c) optionally filtering said polymer solution and optionally said stabilizing solution through a filtration unit; 
 d) mixing the optionally filtered polymer solution with an aqueous solution; 
 e) evaporating the organic solvent; 
 f) purifying the formed nanoparticles; and 
 g) adding photosensitizer to the solution formed in step a) or to the purified nanoparticles formed in step f). 
 
     
     
       8. The method according to  claim 7 , characterized in that the stabilizing solution includes polyvinylalcohol. 
     
     
       9. The method according to  claim 7 , characterized in that the composition formed in step g) is freeze dried in the presence of cryoprotective agents. 
     
     
       10. The method according to  claim 9 , characterized in that the cryoprotective agents are selected from the group consisting of glucose, trehalose, sucrose, sorbitol, mannitol and combinations hereof. 
     
     
       11. The method according to  claim 7 , characterized in that the organic solvent used in step a) is a water-miscible compound. 
     
     
       12. The method according to  claim 11 , wherein the water miscible compound is acetone. 
     
     
       13. The method according to  claim 7 , characterized in that the organic solvent used in step
 a) is a water immiscible solvent. 
 
     
     
       14. The method according to  claim 13 , wherein the water immiscible solvent is dichloromethane. 
     
     
       15. A method of treating a patient with photodynamic therapy comprising administering light and a photsensitizer to the patient, wherein the photosensitizer comprises the pharmaceutical formulation of  claim 2 . 
     
     
       16. The method of  claim 15 , wherein the photodynamic therapy treats a condition selected from the group consisting of tumors, other neoplastic diseases, dermatological disorders, opthalmological disorders, urological disorders and arthritis.